Conformationally rigid bicyclic and adamantane derivatives useful as α2-adrenergic blocking agents

ABSTRACT

A compound of formula I                    
     in which: ring A is one of the five alternative multi-cyclic rings as shown wherein a dotted line adjacent to a bond indicates that a single bond or a double bond may be present at that position; X is nitrogen, oxygen or sulfur; R is hydrogen, lower straight or branched chain alkyl of 1 to 6 carbon atoms, or lower straight or branched chain alkenyl of 2 to 6 carbon atoms, a cycloaliphatic ring of 3 to 6 carbon atoms, phenyl optionally mono- or di-substituted with hydroxy, halogen, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 2 carbon atoms, or methylenedioxyphenyl; or a stereoisomer, or a pharmaceutically acceptable salt thereof. 
     These compounds have α 2  receptor blocking activity and hence find use in the treatment or palliation of elevated intraocular pressure, non insulin-dependent diabetes, male impotence and obesity.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of Serial No. 09/003,902 filedJan. 7, 1998 now U.S. Pat. No. 6,150,389; which is a CIP of Serial No.08/538,694 filed Oct. 3, 1995, now U.S. Pat. No. 5,731,337; which is aFWC of 08/273,521 filed Jul. 11, 1994, now abandoned.

FIELD OF THE INVENTION

The present invention relates to aliphatic bridged cyclic compounds with2-amino-imidazoline, 2-amino-oxazoline or 2-amino-thiazolinesubstituents. More particularly, the invention relates to such.compounds which are selective in blocking the α₂ adrenoreceptor. Thesecompounds find use in the treatment of conditions which are responsiveto regulation of α₂-receptor responses, such activities include, forexample, treatment of depression, palliation of non insulin-dependentdiabetes, alleviation of male impotence, lowering of intraocularpressure (which is useful in treating e.g. glaucoma) and stimulation ofweight loss.

BACKGROUND OF THE INVENTION

Adrenergic agents, and particularly agents affective on α₂ adrenergicreceptors are known in the art. For example, U.S. Pat. No. 5,091,528describes 6- or 7-(2-imino-2-imidazoline)-1,2-benzoxazine as aadrenergic agents. Published European patent application 0 251 453describes certain cyclohexyl substituted amino-dihydro-oxazoles,-thiazoles and -imidazoles as α₂ agents. U.S. Pat. No. 3,598,833describes 2-cycloalkylamino oxazolines having local anesthetic,sedative, vasoconstrictor, mucous membrane de-swelling, blood pressuredepressant and gastric fluid secretory inhibition effects. FurtherUnited States and foreign patents and scientific publications whichpertain to substituted amino-oxazoline, imidazolines and thiazolines areas follows:

U.S. Pat. No. 4,587,257 [2-trisubstituted phenylimino) imidazolinecompounds capable of controlling ocular bleeding];

U.S. Pat. No. 3,636,219 [2-(substituted-phenylamino)-thiazolines andimidazolines having anticholinergic activity];

U.S. Pat. No. 3,453,284 [2-substituted anilino)-2-oxazolines;

U.S. Pat. No. 3,432,600 [partially reduced 2-(naphthylamino) oxazolinesand 2-(indanylamino) oxazolines;

U.S. Pat. No. 3,679,798 [compositions comprising arylaminooxazolines andan anticholinergic agent];

U.S. Pat. No. 3,624,092 [amino-oxazolines useful as central nervoussystem depressants];

U.S. Pat. No. 2,876,232 [2-(9-fluorenylamino)-oxazolines), and GermanPatent nos. 1,191,381 and 1,195,323 and European Patent Application no87304019.0;

U.S. Pat. No. 4,515,800 [2-(trisubstituted phenylimino) imidazolinecompounds, also known as2-(trisubstituted-anilino)-1,3ldiazacyclopentene-(2) compounds, fortreatment of glaucoma];

U.S. Pat. No. 5,066,664 [2-(hydroxy-2-alkylphenylamino)-oxazolines andthiazolines as anti glaucoma and vasoconstrictive agents].

Chapleo et al. [Journal of Medicinal Chemistry 1989, 32, 1627-30]describe heteroaromatic analogs of clonidine as partial agonists of α₂adrenoceptors.

Poos, et al. [Journal of Organic Chemistry, 1961, 26, 4898-904.]reported the syntheses of isomeric forms of 2-amino-3-phenylnorbornanes,and that the endo-phenyl-exo-amino compounds demonstrated a biphasiceffect on blood pressure. U.S. Pat. No. 3,514,486 to Hartzler disclosesmaking 3-isopropyl-2-norbornanamine and reports that they have usefulantihypertensive activity.

Additionally, commonly assigned co-pending applications Ser. Nos08/186,406 and 08/185,653 disclose alpha-substituted derivatives ofaromatic 2-amino-imidazoles and methods of using the same as α_(2A)selective agonists.

The background of the division of adrenoceptors into differingcategories can be briefly described as follows. Historically,adrenoceptors were first divided into α and β subtypes by Ahlquist in1948. This division was based on pharmacological characteristics. Later,β-adrenoceptors were subdivided into β₁ and β₂ subtypes, again based ona pharmacological definition by comparison of the relative potencies of12 agonists. The α-adrenoceptors were also subdivided into α₁ and α₂subtypes, initially based on a presumed localization of α₁ receptorspostsynaptically and α₂ presynaptically. Now, however, this physiologicdivision is no longer used and it is generally accepted that the mostuseful way to subdivide the a-adrenoceptors is based on pharmacology,using affinities for the a-antagonists yohimbine and prazosin. At α₁receptors, prazosin is more potent than yohimbine, whereas at α₂receptors, yohimbine is more potent than prazosin. More recently the α₁and α₂ receptors have been further subdivided into subtypes such asα_(1A), α_(1B), α_(1C), α_(2A), α_(2B) and α_(2C).

The term agonist refers to a class of compounds which bind with someaffinity to and activate a particular type of receptor. Activationrefers to what could be considered analogous to flipping on a switch,i.e. the receptor is induced to initiate some kind of action like aphysiologic response or a chain of biochemical events. The termantagonist (or receptor blocker) refers to a class of compounds whichbind to a receptor with some affinity, but are unable to activate thereceptor to provide an effect. The antagonist can be compared to a keywhich is able to slide into a lock, but is unable to turn in the lock toopen it.

Some examples of alpha₂ (α₂) adrenergic receptor blocking compoundsknown in the art are:

Idazoxan is classified as a selective α₂ antagonist, and has beenstudied in combination with tyrosine as an antidepressant and incombination with D₂ dopamine receptor antagonists as an antipsychoticagent.1,2,3,4-tetrahydro-6hydroxy-1-((N-methyl-amino)-methyl-N-phenylethyl)naphthalenehydrochloride (A-75169) lowers intraocular pressure in mammals.

The receptor affinity of candidate compounds can be determined byradioligand binding competition studies. Radioligand binding competitionstudies assess the affinity of a compound by measuring its ability todisplace a radioligand of known affinity.

As described above, an agonist is defined as a compound that binds toand activates a receptor response. An antagonist binds to, but does notactivate a response by, the receptor. The measure of activation causedby a bound molecule is said to be its efficacy. Functional experimentsare designed to determine whether, after binding, a test compoundelicits a biochemical effect, or rather binds without causing thereceptor to respond. An antagonist, if of sufficient binding affinity,can be used to block the binding of endogenous molecules in the bodywhich activate a receptor, and thereby prevent its activation.Antagonists can find therapeutic use by blocking the binding of anoversupply of an endogenous receptor activator or the over expression ofa receptor effect. Owing to the intricacy of the interactions between agiven binding molecule and the conformation and function of the receptoritself, partial agonists and partial antagonists are also known inreceptor pharmacology.

SUMMARY OF THE INVENTION

The present invention concerns novel compounds of the formula I,

in which: ring A is any of the five alternative multi-cyclic ringsshown, X is nitrogen, oxygen or sulfur and R is hydrogen, straight orbranched chain alkyl of 1 to 6 carbon atoms, or straight or branchedchain alkenyl of 2 to 6 carbon atoms, a cycloaliphatic ring of 3 to 6carbon atoms, phenyl optionally mono- or di-substituted with hydroxy,halogen, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 2 carbon atoms,or methylenedioxyphenyl. In the drawing of chemical structures as shownabove, the intersection of two or more lines indicates a carbon atom, asingle line indicates a single bond, and a double line a double bond,and a dotted line adjacent a single line indicates either a single ordouble bond. The chemical nomenclature for the rings shown above fromleft to right in descending order is norbornane (orbicyclo[2.2.1]heptane); bornane (or1,7,7-trimethyl-bicyclo[2.2.1]heptane); 7-oxa-bicyclo[2.2.1]heptane;bicyclo[2.2.2]octane and adamantane (or tricyclo[3.3.1.13,7]decane). Thewavy lines across a bond indicate that the bond attaches to either the Ror 2-amino-heterocyclic moieties. Any stereoisomers and diastereomerswhich are available by bonding the substituents R and the2-amino-heteroazole moieties to the available valences of theabove-indicated carbons on the rings are contemplated by the invention,as well as the pharmaceutically acceptable salts.

Another aspect of the invention concerns the method of use of thesecompounds in blocking or antagonizing α receptor function.

Other aspects of the invention relate to pharmaceutical compositionscontaining the compounds of the invention in admixture with one or morepharmaceutically acceptable, non-toxic carriers, and to methodspertaining to their use.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein:

The terms “ester” and “amide” refer to and cover any compound fallingwithin the definition of those terms as classically used in organicchemistry.

The term “alkyl” refers to and includes normal and branched chain alkylgroups as well as cydoalkcyl groups. The term “lower alkyl”, unlessspecifically stated otherwise, includes normal alkyl of 1 to 6 carbons,branched-chain alkyl of 3 to 6 carbons and cyclo-groups having 3 to 6carbon atoms. Similarly, the terms “alkenyl” and “alkynyl” includenormal and branched chain as well as cyclo-alkenyl and alkynyl groups,respectively, having 2 to 6 carbons when the chains are normal, and 3 to6 carbons when the chains are branched or cyclic.

The terms endo and exo are used in describing a substituent in spatialrelation to its connection to a bridged ring and refer to the positionof the substituent as either “inside” or “outside” the ring. For thebicycloheptane compounds, endo refers to a substituent attached to thering by a bond that points down and below the general plane of the sixmembered ring, and exo refers to a substituent attached to the ring by abond that points out from and above the general plane of the sixmembered ring.

The terms cis and trans are also used in describing the relativestereochemistry of the substituents of the present invention. Since thecarbon atoms at positions 2 and 3 in the norbornane andbicyclo[2.2.2]octane rings are rigidly fixed by the bicyclic ringstructure there is no bond rotation or alternative conformation of thering system. Thus, the bond between carbon atoms 2 and 3 can be likenedto a double bond in that respect, and so relative stereochemistry can bedescribed with cis indicating that the substituents are located on thesame side of the bond, and trans indicating that the substituents arelocated in positions opposite one another across the bond.

Pharmaceutically acceptable salts of the compounds of formula I are alsowithin the scope of the present invention. Pharmaceutically acceptableacid addition salts of the compounds of the invention are those formedfrom acids which provide pharmaceutically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphateor acid phosphate, acetate, maleate, fumarate, oxalate, lactate,tartrate, citrate, gluconate, saccharate, or p-toluenesulfonate salts. Apharmaceutically acceptable salt may be any salt which retains theactivity of the parent compound and does not impart any deleterious oruntoward effect on the subject to which it is administered and by thecontext in which it is administered.

Organic amine salts may be made with amines, particularly ammonium saltssuch as mono-, di- and trialkyl amines or ethanol amines. Salts may alsobe formed with caffeine, tromethamine, and similar molecules. Wherethere is a nitrogen sufficiently basic as to be capable of forming acidaddition salts such may be formed with any inorganic or organic acids oralkylating agent such as methyl iodide. Any of a number of simpleorganic acids such as mono-, di-, or tri-acid may also be used. Apharmaceutically acceptable salt may be prepared for any compound of theinvention having a functionality capable of forming such a salt, e.g.,an acid salt of an amine functionality.

Utility and dosage forms

The compounds of formula I and pharmaceutically acceptable acid additionsalts thereof have been found to possess valuable pharmacologicproperties in the central nervous system and, in particular, have beenshown to block (antagonize) α₂ receptors in standard laboratory tests.Accordingly, these compounds and pharmaceutically acceptablecompositions containing them are useful in reduction or maintenance ofthe intraocular pressure in at least one eye of a mammal and inregulation of other physiologic phenomena related to α₂ receptors. Suchphysiologic activities include for example: alleviation, prevention orinhibition of depression in mammals; reduction in the severity ofdiabetes; alleviation of male impotence; and stimulation of weight loss.

In applying the compounds of the invention to treatment of diseases ordisorders of the eye which are associated with an abnormally highintraocular pressure, administration may be achieved by anypharmaceutically acceptable mode of administration which providesadequate local concentrations to provide the desired response. Theseinclude direct administration to the eye via drops and controlledrelease inserts or implants, as well as systemic administration asdescribed below.

Drops and solutions applied directly to the eye are typically sterilizedaqueous solutions containing 0.001% to 10%, most preferably 0.005% to 1%of the active ingredient, along with suitable buffer, stabilizer, andpreservative. The total concentration of solutes should be such that, ifpossible, the resultant solution is isotonic with the lachrymal fluidand has a pH in the range of 6-8. Typical sterilizing agents arethimerosal, chlorobutanol, phenyl mercuric nitrate and benzalkoniumchloride. Typical buffers are, for example, citrate, phosphate, borateor tromethamine; suitable stabilizers include glycerin and polysorbate80. The aqueous solutions are formulated by simply dissolving thesolutes in a suitable quantity of water, adjusting the pH with suitableadd or base to a pH of about 6.8 to 8, making a final volume adjustmentwith additional water and sterilizing the resultant solution.

The dosage level of the resulting composition will, of course, depend onthe concentration of the drops, the condition of the subject and theindividual magnitude of response to treatment. However, a typical ocularcomposition could be administered at the rate of about 2 to 10 drops perday per eye of a 0.1% solution of active ingredient.

The compounds of the present invention, when administered for conditionswhich are regulated by the central nervous system (CNS), can be by anyof the accepted modes of administration for agents which relievedepression or affect the CNS including oral, parenteral, rectal, andotherwise systemic routes of administration. Any pharmaceuticallyacceptable mode of administration can be used, including solid,semi-solid, or liquid dosage forms, such as for example, tablets,suppositories, pills, capsules, powders, liquids suspensions, or thelike, preferably in unit dosage form suitable to single administrationof precise dosages, or in sustained or controlled release forms for theprolonged administration of the compound at a predetermined rate. Thecompositions will typically include a conventional pharmaceuticalcarrier or excipient and an active compound of formula I or thepharmaceutically acceptable salts thereof and, in addition, may includeother medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

The of amount of active compound administered will course be dependenton the subject being treated, the severity on the affliction, the mannerof administration and the judgment of the prescribing physician.However, an effective dosage is in the range of 0.01-1 mg/kg/day,preferably 0.1-0.5 mg/kg/day. For an average human of about 70 kg, thiswould amount to 0.7-70 mg/day.

For solid compositions, conventional non-toxic carriers include, forexample mannitol, lactose, starch, magnesium stearate, sodium saccharin,talcum, cellulose, glucose, sucrose, magnesium carbonate, and the likemay be used. The active compound as defined above may be formulated assuppositories using, for example, polyalkylene glycols, for example,propylene glycol as a carrier. Liquid pharmaceutically administerablecompositions can, for example, be prepared by dissolving, dispersing,etc. an active compound as defined above and optional pharmaceuticaladjuvants in a carrier, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of non toxic auxiliary pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine oleate, etc. Actual methods of preparingsuch dosage forms are known, or will be apparent to those skilled inthis art; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 15th Edition, 1975. The composition orformulation to be administered will, in any event, contain a quantity ofthe active compound in an amount effective to alleviate the symptoms ofthe subject being treated.

Dosage forms or composition containing active ingredient of formula I orits salts in the range of 0.25 to 95% with the balance made up fromnon-toxic carrier may be prepared.

For oral administration, a pharmaceutically acceptable non-toxiccomposition is formed by the incorporation of any of the normallyemployed excipients, and may contain 1% -95% active ingredient,preferably 5% -50%.

Parenteral administration is generally characterized by injection,whether subcutaneously, intramuscularly, or intravenously. Injectablescan be prepared in conventional forms, either as liquid solutions orsuspension, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients include, forexample, water, saline, aqueous dextrose, glycerol, ethanol or the like.In addition, if desired, the pharmaceutical compositions may alsocontain minor amounts of non-toxic substances such as wetting oremulsifying agents, auxiliary pH buffering agents and the like, forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleate,etc.

The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject. However,percentages of active ingredient of 0.1% to 10% in solution areemployable, and will be higher if the composition is a solid which willbe subsequently diluted to the above percentages. Preferably thecomposition will comprise 0.2-2% of the active agent in solution.

PREFERRED EMBODIMENTS

Among the family of compounds of the present invention, a preferredgroup includes compounds of formula I wherein X is oxygen, i.e.compounds where the oxazoline ring constitutes the heterocycle.

A second preferred group of compounds of the invention are those thatincorporate the bicyclo[2.2.1]heptane group in their structure as thering A group.

Within either of the two preceding preferred groups, a still morepreferred embodiment is of compounds which have a hydrogen atom or anaromatic group at the position represented by R.

METHODS OF PREPARATION

As illustrated by Scheme I below, treatment of an alkynyl acid withdiazomethane in ether afforded the corresponding ester. The ester andcyclopentadiene were warmed at 175° C. for 40 hours to form thecycloadduct. This adduct was unstable to SiO₂ chromatography and wasbest purified using a Kugelrohr distillation.

The double bonds in the cycloadduct were immediately saturated bytreatment with H₂ and Pd/C at one atmosphere. Conversion of the esterinto an amine was accomplished by conversion to the carboxylic acidfollowed by a Curtius reaction. Thus, the acid was activated bytreatment with isobutylchloroformate. The acyl azide was formed bytreatment with sodium azid,e. Elimination of nitrogen and formation of abenzyl carbamate occurred when the azide was warmed in toluene in thepresence of benzyl alcohol. The amine was liberated upon treatment withH₂ and Pd/C at one atmosphere. Oxazoline synthesis was accomplishedunder standard conditions: treatment first with chloroethylisocyanateand then aqueous NaHCO₃ solution.

endo, exo Relative stereochemistry

Preparation of b-nitrostyrene was accomplished according to the OrganicSyntheses method. Treatment of a methanol solution of benzaldehyde withnitromethane (100 mol.-%) in the presence of sodium hydroxide (105mol.-%) afforded the nitro alcohol. Dehydration of the alcohol waseffected by treatment with aqueous hydrochloric acid (5M).

The nitrostyrene of 3,4dihydroxybenzaldehyde was obtained by treatingpiperonal (3,4-methylenedioxybenzaldehyde) in a similar fashion to thatreported for b-nitrostyrene. The acetal proved stable to the aqueousacid required for dehydration.

Construction of the bicyclo[2.2.1]heptane skeleton was carried out intwo steps. The Diels-Alder reaction was conducted by warming thenitrostyrene with cyclopentadiene (110 mol.-%) neat (b-nitrostyrene is alow melting material) or in 1,2-dichloroethane (1M in nitroolefin). TheDiels-Alder reaction proceeds in approximately a 3:1 endo nitro: exonitro ratio. Both the ratio and relative stereochemistry wasdemonstrated through X-ray analysis. Reduction of both the nitro groupand the olefin was carried under an atmosphere of hydrogen in thepresence of 10 weight-% palladium on charcoal (10%). Separation ofisomers was conveniently carried out at this stage using flashchromatography.

Oxazoline synthesis was conducted under standard conditions. The aminewas first converted to the chloroethylurea by treatment withchloroethylisocyanate. Warming the chloroethylurea in the presence ofsodium bicarbonate afforded the oxazolines. This effort is summarized inScheme II. Thiazolines and imidazolines were also prepared understandard conditions. Treatment of amines with chloroethylisothiocyanateaffords thiazolines directly while treatment with imidazoline-2-sulfonicacid affords the corresponding imidazolines in a single step.

Reagents and Conditions: i. CH₃NO₂, KOH, MEOH; ii. HCl; iii.cyclopentadiene, neat or 1M in dichloroethane; iv. H₂, 10 Pd on C; v.chloroethylisocyanate; vi. NaHCO₃ [X═O]; vii. chloroethylisothiocyanate[X═S]; viii. imidazoline-2-sulfonic acid [X═NH].

Synthesis of oxabicyclo[2.2.1]heptane derivatives of the presentinvention can also be prepared by Diels Alder reactions following meanswell known in the art. Grieco, Zelle, Lis and Finn in Journal of theAmerican Chemical Society, 105, 1403-4 (1985) report means of makingsuitably derivatized oxabicyclo[2.2.1]heptane andoxabicydo[2.2.1]heptene compounds which can be elaborated into compoundsof the present invention. This can be accomplished by the syntheticsteps which follow the Diels Alder cyclo addition in Scheme 1 using the2-carbomethoxy-bicyclo[2.2.1]hept-2-ene intermediate of the reference,or if the nitro functionality of other of the Grieco et al. compoundsare employed, according to the steps iv, v, vi (or vii or viii) inScheme 2. Another journal article by Jarvest and Readshaw discloseadvantageous conditions for Diels-Alder cyclization of derivatizedfurans and cyanoacrylate to yield2-cyano-5-substituted-bicyclo[2.2.1]heptanes. These articles areincorporated by reference herein in their entirety.

The invention is further illustrated by the following non-limitingexamples which are illustrative of a specific mode of practicing theinvention and are not intended as limiting the scope of the appendedclaims.

EXAMPLE 1 2-Hydroxy-1-nitrohexane

Pentanal (49.6 ml, 464 mmol) was stirred in a solution of nitromethane(276 ml, 5108 mmol). To the reaction methanolic KOH (3N) was addeddropwise to pH 8. The reaction was stirred at room temperatureovernight. The solution contained trace amounts of insoluble dark brownmaterial. The solution was washed with H₂O and extracted intodichloromethane; concentration of the solvent gave clean product (II) in96% yield, (56.58 g).

EXAMPLE 2 1-Nitrohex-1-ene

The nitroalcohol (1) (2.0 g, 13.6 mmol) was dissolved in dichloromethaneand treated at 0° C. for 30 minutes by dropwise addition withmethanesulfonyl chloride (1.6 g, 13.6 mmol). Triethylamine (2.75 g, 27.2mmol) was then added dropwise and stirred for an additional hour at 0°C. The product was washed with 1M H₃PO₄ and then with saturated NaHCO₃and extracted with dichloromethane. Concentration of the solvent gavethe olefin in 80% yield (3.03 g).

EXAMPLE 3 Trans 2-nitro-3-butyl bicyclol[2.2.1]heptane

The nitroolefin (2) (3.00 g, 19.3 mmol) was dissolved in 20 ml ofdichloromethane and then freshly cracked cyclopentadiene (6.49, 96.6mmol) was added and bubbled with argon for 15 minutes. This was added toa sealable tube and. once sealed was placed in an oil bath at 90° C.overnight. The reaction went to completion. Excess cyclopentadiene wasremoved by Kugelrohr distillation. The resultant product was obtained in60% yield (353 g).

EXAMPLE 4 Trans 2-(3butyJ-bicyclo[2.2.1]heptyl)amine

The cycloadduct (3) (2.53 g, 13.0 mmol) was dissolved in methanol (25ml) and bubbled with Ar. To this was added 10% palladium on carbon (500mg). This vessel containing this mixture was put on a Parr apparatus forhydrogenation at 50 psi overnight. The reduced material was filteredthrough celite and the solvent was concentrated. The residue wasdissolved in 1M H₃PO₄ and washed with dichloromethane. The aqueous layerwas basified with 25% NaOH to a pH of ca. 13. This was extracted withdichloromethane three times. The organic layers were combined andconcentrated to give the product in 86% yield (1.86 g).

EXAMPLE 5A Trans 2-(3-butyl bicyclo[2.2.1]heptyl)amino-oxazoline

The amine (4) (200 mg, 1.20 mmol) was dissolved in TEF (5 ml). To thiswas added chloroethylisocyanate (0.122 ml, 1.40 mmol) dropwise andstirred at room temperature for two hours. The reaction mixture waspoured into 1M H₃PO₄ and ice (1:1) to quench the reaction. This was thenextracted with dichloromethane and concentrated to give the urea. Theurea was treated with methanol (6 ml), water (6 ml) and NaHCO₃ (202 mg,2.4 mmol). This mixture was refluxed at 80° C. for 2 hours. The reactionwas quenched with saturated NaHCO₃ and extracted with dichloromethane.The organic layers were combined and concentrated to give desiredproduct (270 mg). Column chromatography with 5% MeOH saturated with NH₃in dichloromethane gave the desired product in 60% yield (155 mg).

¹H NMR(CDCl₃): 0.70-1.70(M,16H), 1.9(d, 1H), 2.5(5, 1H), 3.4(S1H)3.75(t,2H), 4.1(5,1H), 4.25(t,2H). Elemental analysis:theoretical - C71.14% H 10.23% N 11.86% found - C 70.8% H 10.20% N 11.60%

5B.

Trans 2-(3-butyl-bicyclo[2.2.1]heptyl)aminothiazoline

The amine (4) (200 mg, 1.20 mmol) in THF (5 ml) was treated withchloroethylisothiocyanate dropwise at 0° C. for 3 hours. The reactionmixture was poured into 1M H₃PO₄. The aqueous layer was extracted withdichloromethane and then basified with 25% NaOH to pH 13. The aqueouslayer was then extracted with dichloromethane three times. The organiclayers were combined and concentrated to give the product in 11.6% yield(35 mg).

¹H NMR (CDCl₃): 0.85 (t, 3H), 1.1-1.7(M, 13H), 1.95 (d,1H), 2.5 (S, 1H)3.3 (t,2H), 3.5 (S,1H), 4.0 (t, 2H)

¹³C NMR C (CD₃OD): d 14.0, 21.0, 23.0, 30.0, 30.5, 35.0, 35.2, 35.3,40.5, 41.5, 51.5, 64.0. Elemental analysis: theoretical - C 66.63% H9.59% N 11.10% found - C 66.40% H 9.52% N 11.0%

5C.

Trans 2-(3-butyl-bicyclo[2.2.1]heptyl)aminoimidazoline

An acetonitrile (2.4 ml) suspension of the amine (4) (200 mg, 1.20 mmol)with triethylamine (0.184 ml, 1.32 mmol) and then withimidazoline-2-sulfonic acid (198 mg, 1.32 mmol). The solution wasrefluxed for 2 hours. Aqueous workup with 1 M H₃PO₄ and then basifyingaqueous layer to pH 13 and extraction with dichloromethane gave thedesired product. The HCl salt was prepared from HCl/ether in methanolwhich gave a yield of 20% (60 mg).

¹H NMR (CDCl₃): 0.70-1.70 (M, 16H), 2.0 (d, 1H), 2.6 (S,1H), 3.4(S,1H)3.65(S,4H) ¹³C NMR (CHCl₃): d 22.9, 27.8, 27.89, 28.05, 31.83, 32.29,33.41, 37.34, 39.89, 4253, 42.89, 44.06, 44.54, 57.9, 61.6, 95.6,161.02.

EXAMPLE 6A exo-[2.2.1]bicycloheptyl-2-amino-oxazoline

A THF solution containing the exo-norbornylarnine was cooled to 0° C.under a nitrogen atmosphere and was treated with chloroethylisocyanate.The magnetically mixed solution was allowed to warm to r.t. over 1 h andthen stirred an additional 1 h at r.t. After extraction from 1 M H₃PO₄(20 mL; 3×15 mL CH₂Cl₂ extraction) and drying over Na₂SO₄ the whitesolid recovered after concentration was warmed at reflux in aqueous MeOHcontaining NaHCO₃. After extraction from 0.5N NaOH, drying (Na₂SO₄)concentration and chromatography (eluent: 5% NH₃-saturated MeOH inCH₂Cl₂; 230-400 mesh SiO₂; eluate collected in 10 mL fractions).Fractions 10-20 afforded 350 mg of the agent (65%). Recrystallizationwas accomplished using pure hexane.

mp 115-117° C.

¹H-NMR (CDCl₃): 0.87 (t over m, 5H), 1.1-1.85 (m, 5H), 2.4 (s,1H), 3.78(t, 2H), 3.85 (s, 1H), 4.25 (t, 2H). Example 6B endo-[12.2.1]bicycloheptyl-2-amino-oxazoline

The amine from Aldrich (as H Cl salt was dissolved in 25% NaOH andextracted 3 times with CH₂Cl₂, dried over Na₂SO₄ and concentrated to awaxy foam, dried under vacuum, and treated with choloethylisocyanate aswith the exo amine above in 6A.

mp 122-124° C.

¹H-NMR (CDCl₃): 1.08-1.26 (m, 5H), 1.32-1.85 (m, 5H), 2.28 (br. d,1H),3.45 (s, 1H), 3.79 (t, 2H), 4.24 (t, 2H).

EXAMPLE 7 2-Carbomethoxy-3-ethyl [2.2.1] bicyclo Δ^(2,3), Δ^(5,6)heptadiene

Methyl pent-2-ynoate (5.3 g, 126.16 mmol) was dissolved in toluene (30ml) and placed in a sealable tube. To this was added freshly crackedcyclopentadiene. The tube was sealed and placed in a oil bath at 168° C.for 42 hours. The excess cyclopentadiene was removed by Kugelrohrdistillation. The product was isolated in 70.3% yield (5.26 g).

EXAMPLE 8 Cis 2-carbomethoxy-3-ethyl[2.2.1]bicycloheptane

The cycloadduct (6) (5.26 g, 295 mmol) was dissolved in MeOH (60 ml) andbubbled with Ar, and to the solution was added 10% palladium on carbon(500 mg). The reaction vessel containing this mixture was put on a Parrapparatus for hydrogenation at 50 psi overnight. The reduced materialwas filtered through celite and solvent concentrated. The residue wasdissolved in 1M H₃PO₄ and washed with dichloromethane. The aqueous layerwas basified with 25% NaOH to ca. pH 13. This was extracted withdichloromethane three times. The organic layers were combined andconcentrated to give product in 81% yield (4.7 g).

EXAMPLE 9 Cis 2(3ethyl-bicyclo[2.2.1]heptyl) amine

The ester (3) (2.0 g, 10.2 mmol) was dissolved in a MeOH/THF (30 ml/20ml) solution. This was treated with 2N LiOH (10.2 ml, 20.4 mmol) in H₂Oat 100° C. and refluxed. The reaction was concentrated to a paste anddissolved in 40 ml H₂O and washed twice with dichloromethane. Theorganic layers were combined and concentrated to give the correspondingacid. This acid was dissolved in acetone (20 ml), and triethylamine(3.06 ml, 22.1 mmol) was added dropwise. Next ethylchloroformate wasadded dropwise (2 ml, 20.9 mmol) at 0° C. The reaction was stirred for 1hour. NaN₃ (676 mg, 10.4 mmol) was added in portions at 0° C. for anadditional hour. The reaction was partitioned between ice water anddichloromethane. The organic layers were combined and concentrated togive the acyl azide. This was then treated with benzyl alcohol (995 mg,9.2 mmol) in toluene and refluxed at 110° C. for 30 minutes. Thereaction was washed with H₂O and extracted in dichloromethane.Concentration of solvent gave the benzyl carbamate. The carbamate wasreduced in the same manner as before with 10% palladium on carbon. Theproduct was obtained in an overall yield of 45% (550 mg).

NMR H¹(CDCl₃): 0.8(t, 3H), 1.0-1.6(m, 9H), 1.8 (s,1H), 2.2 (s,1H),4.7(s,1H), 5.3(s,2H)

EXAMPLE 10A Cis 2-(3-ethyl-bicyclo[2.2.1]heptyl) amino-oxazoline

The bicyclic amine (8) was treated as in the procedure outlined for thepreparation of the trans compound (5A) above.

¹H-NMR (CDCl₃): 0.8(t, 3H), 1.00-2.00(m, 9H), 2.1(s,1H), 2.5(s,1H),3.9(s,1H), 3.8(t, 2H), 4.2(t, 2H). ¹³C NMR (CDCl ₃): d 14.5, 20.8, 25.5,28.2, 382, 40.3, 44.7, 54.42, 55.05, 64.3, 69.2. Analysis calculated forC₁₂H₂₀N₂O: C 69.09, H 9.68, N 13.45 Found: C 68.6, H 9.24, N 13.45.

EXAMPLE 10B Cis 2-(3-ethyl bicyclo[2.2.1]heptyl) aminothiazoline can beprepared by substituting the bicyclic amine (8) for (4) in thepreparation of 5B above. EXAMPLE 10C Cis 2-(3ethyl-bicyclo[2.2.1]heptyl)aminoimidazoline

Likewise, 9C can be prepared by substituting the bicyclic amine (8) for(4) in the preparation of 5C above.

EXAMPLE 11 2-N-Bornylamino-oxazoline

To a THF solution of the amine (250 mg, 1.63 mmol) at 0° C. was addedchloroethylisocyanate (189 mg, 1.79 mmol) dropwise. The reaction wasallowd to warm to r.t. and after stirring for one hr., all startingmaterial was consumed. The reaction mixture was poured into 1M H₃PO₄ andextracted three times with methylene chloride. After drying, thesolution was concentrated and the resulting solid was warmed in aqueousmethanolic NaHCO₃. The reaction was extracted from 0.5N NaOH and dried(Na₂SO₄), concentrated and chromatographed over 250-400 mesh silicausing 5% ammonia saturated methanol in CH₂Cl₂ as eluent. Yield: 206 mg(60%).

¹³C NMR (CDCl₃) 161.7, 67.6, 57.8, 52.9, 49.2, 48.0, 44.8, 38.4, 28.3,27.6, 19.9, 18.7, 13.7 ¹H NMR (CDCl₃) 4.24 (2H, m); 3.80 (3H, m); 2.38(1H,m); 1.87-1.1 (6H, env, m); 0.93 (3H, s); 0.87 (3H, s); 0.86 (3H, s)

EXAMPLE 12 Bicyclo[2.2.2]octane aminooxazoline Adamantylaminooxazoline

In a similar manner to Example 10, commercially availablebicyclo[2.2.2]octane amine and adamantylamine can be used to prepare the2-bicyclo[2-2.2]octane-aminooxazoline and adamantylaminooxazolinecompounds, respectively.

EXAMPLE 13 Receptor Binding Assays

13 A.

Tissue preparation: Membrane suspensions were prepared from humancerebral cortex (HCC) obtained from the UCI Organ and Tissue Bank andrat kidney cortex (RKC). Briefly, tissues (1 g) were homogenized in 25ml of iced-cold 5 mM tris, pH 7.4 with a Polytron homogenizer for 30secs at setting #7, and centrifuged for 10-12 minutes at 300 ×g at 4° C.The supernatant was filtered through 2 layers of gauze and diluted 1:2with 50 mM Tris-HCl buffer, pH 7.4, then centrifuged at 49,000 ×g for 20minutes. The pellet fraction was washed 3 times (resuspended in Tris-HClbuffer and centrifuged for 20 minutes at 49,000 ×g). The pellet was thenstored at −800° C. until the binding assay.

Cell preparation: HT-29 and chinese hamster ovary (CHO) cells expressingthe human α_(2A) (CHO-C10) receptor and CHO cells (CHO-RNG) expressingthe rat α_(2B) adrenoceptor were grown to near confluency in Dulbecco'smodified Eagle's medium supplemented with 10% fetal bovine serum usingstandard cell culture methods. Cells were harvested by scraping andplaced into cold buffer of the following composition: 50 mM Tris-HCl, 5mM EDTA, pH 7.4). Cells were then homogenized with a Polytronhomogenizer for 2×10 secs at setting #7, and centrifuged for 20 minutesat 49,000×g. The pellet fraction was washed (resuspended in Tris-HCl, pH8 buffer and centrifuged for 15-20 minutes at 49,000×g) 2 times andstored at −1000° C. until binding assay.

Binding studies: The radioligands [³H]rauwolscine (specific activity 80Ci/mmol) and [³H]prazosin (specific activity 76 Ci/mmol) were obtainedfrom New England Nuclear, Boston, Mass. Frozen membrane pellet wasresuspended in 25 mM glycine/glycine, pH 7.4 and incubated withradioligand under the following conditions: CHO-C10, CHO-RNG,HT-29-[³H]rauwolscine, 22° C., 30 minutes; RKC-[³H]rauwolsdne, 0° C.,120 minutes; and, HCC-[³H]prazosin, 22° C., 30 minutes in a final volumeof 500 μl. At the end of the incubation period, the samples werefiltered through glass fiber filters (Whatman GF/B) in a 96 well cellharvester and rapidly washed four times with 4 ml of ice-cold 50 mMTris-HCl buffer. The filters were then oven dried and transferred toscintillation vials containing 5 ml of Beckman's Ready Protein®scintillation cocktail for counting. Specific binding defined by 10 μMphentolamine for competition studies were as follows: 0.3 nM[³H]rauwolscine—CHO-C10 99%; 0.4 nM [³H]frauwolscine—CHC-RNG 99%; 0.7 nM[³H]rauwolscine—HT-29 90%; 1 nM [³H]rauwolscine—RKC 92%, and 0.3 nM[³H]prazosin—HCC 87%. Protein concentrations were determined with aprotein assay kit from Bio Rad. Binding isotherms, equilibriumdissociation and affinity constants were analyzed and determined by thenon-linear least squares curve fitting programs AccuFitCompetition/Saturation by Beckman.

Binding studies: The radioligands [³H]rauwolscine (specific activity 80Ci/mmol), [³]prazosin (specific activity 76 Ci/mmol) and [³H]brimonidine(UK-14,304; specific activity 63 Ci/mmol) were obtained from New EnglandNuclear, Boston, Mass. Frozen membrane pellet was resuspended in either50 mM tris, 2 mM EGTA, 1 mM MgCl₂, pH 7.5 (RbKC, RbICB-[³H]brimonidine);50 mM tris, 0.5 mM EDTA, 5 mM NaCl, pH 7.7 (RbICB-[³H]rauwolscine); 25mM glycine/glycine, pH 7.4 (RtKC, CHO-C10, CHO-RNG, HT-29, HCC) or 50 mMtris, 0.1 mM MnCl₂, pH 7.7 (RtCC). Membrane protein homogenate (75-200μg) was incubated with radioligand under the following conditions: RbKCand RbICB-[³H]rauwolscine, 22° C., 45 minutes; RtCC andRbICB[³H]brimondine, 22° C., 90 minutes; CHO-C10, CHO-RNG andHT-29-[³H]rauwolscine, 22° C., 30 minutes; HCC-[³H]prazosin, 22° C., 30minutes; and, in a final volume of 250 or 500 μl. At the end of theincubation period, the samples were filtered through glass fiber filters(Whatman GF/B) in a 24 or 96 well cell harvester and rapidly washed fourtimes with 4 mls of iced-cold 50 mM Tris-HCl buffer. The filters werethen oven dried and transferred to scintillation vials containing 10 mlsof Beckman's Ready Protein® scintillation cocktail for cotg. Specificbinding defined by 10 μM phentolamine for competition studies were asfollows: 2.4 nM [³H]brimonidine-RbICB 62%; 2.4 nM [³H]rauwolscine-RbICB75%; 2 nM [³H]rauwolscine-RbKC 88%; 0.3 nM [³H]rauwolscine-CHO-C10 99%;4.0 nM [³H]rauwolscine-CHO-RNG 99%, 0.3 nM [³H]prazosin 87%; and 1 nM[³H]rauwolscine-RtCC 90%. Protein concentrations were determined with aprotein assay kit from Bio Rad. Binding isotherms, equilibriumdissociation and affinity constants were analyzed and determined by thenon-linear least squares curve fitting programs EBDA (BioSoft) orAccuFit Competition/Saturation by Beckman.

13 B.

Cell preparation: Chinese hamster ovary (CHO) cells expressing the humanα_(2A) (CHO-C10) and the rat α_(2B) (CHO-RNG) adrenoceptors were grownto near confluency in Dulbecco's modified Eagle's medium supplementedwith 10% fetal bovine serum using standard cell culture methods. Cellswere harvested by scraping and placed into cold buffer of the followingcomposition: 50 mM Tris-HCl, 5 mM EDTA, pH 7.4). Cells were thenhomogenized with a Polytron homogenizer for 2×10 secs at setting #7, andcentrifuged for 20 minutes at 49,000×g. The pellet fraction was washed(resuspended in Tris-HCl, pH 8 buffer and centrifuged for 15-20 minutesat 49,000×g) 2 times and stored at −100° C. until binding assay.

13C.

Binding studies: Determination of K_(i)

The radioligands [³H]rauwolscine (specific activity 80 Ci/mmol) and[³H]prazosin (specific activity 76 Ci/mmol) were obtained from NewEngland Nuclear, Boston, Mass. Frozen membrane pellet was resuspended in25 mM glycine/glycine, pH 7.4 and incubated with radioligand under thefollowing conditions: CHO-C10, CHO-RNG —[³H]rauwolscine, 22° C., 30minutes; and, HCC-[³H]prazosin, 22° C., 30 minutes in a final volume of500 ul. At the end of the incubation period, the samples were filteredthrough glass fiber filters (Whatman GF/B) in a 96 well cell harvesterand rapidly washed four times with 4 mls of iced-cold 50 mM Tris-HClbuffer. The filters were then oven dried and transferred toscintillation vials containing 5 ml of Beckman's Ready Protein®scintillation cocktail for counting. Specific binding defined by 10 μMphentolamine for competition studies were as follows: 0.3 nM[³H]rauwolscine-CHO-C10 99%.; 0.4 nM [³H]rauwolscine-HO-RNG 99%/e, and0.3 nM [³H]prazosin —HCC 87%. Protein concentrations were determinedwith a protein assay kit from Bio Rad. Binding isotherms, equilibriumdissociation and affinity constants were analyzed and determined by thenon-linear least squares curve fitting programs AccuFitCompetition/Saturation by Beckman.

Determination of α₂ activation: Measuring efficacy (EC₅₀)

Vas Deferens: The prostatic ends of the vas deferens (2-3 cm) wereremoved from albino rabbits and mounted between platinum electrodes in 9ml organ baths containing Krebs-Hensleit solution of the followingcomposition (mM): NaCl 119, KCl 4.7, MgSO₄1.5, KH₂PO₄ 1.2. CaCl2 2.5,NaHCO₃25 and glucose 11. This solution was maintained at 35° C. andbubbled with 95% O₂ and 5% CO₂. The tissue was equilibrated at 05 gtension for 30 minutes. The vas deferens strips were then fieldstimulated at 0.1 Hz, 2 msec, 90 mA using a square wave stimulator(World Precision Instruments A310 Accupulser/A385 Stimulus Isolater), ora Grass S48 stimulator at 0.1 Hz, 2 msec, 70 volts. After 30 minutes ofelectrical stimulation, cumulative concentration-response curves in 0.25log units were obtained with a 4 minute contact time for eachconcentration. Each tissue was used to evaluate only one drug. Tissuecontractions produced by the field stimulation were measuredisometrically using Grass FT-0.03 forcedisplacement transducers andrecorded on a Grass Model 7D physiograph. The reduction inelectrically-evoked peak height by the drugs was measured and expressedas a percentage of the pre-drug peak height. The IC₅₀ was determined asthe concentration which produced a 50% reduction in peak height.

TABLE I K_(i) (nM) Structure α_(2A) (CHO—C10) α_(2B) (CHO- EC₅₀ (nM)tested α₁ (HT-29)* RNG)(RKC)^(†) α₂ (vas def.)

 11,131 1,751 4,174 >56,200

  1,864 3.1 7.8  29,000

  6.730 14.3    72 >56,200

 10,977 6,571 6,103 not tested as no binding was observed

    73 1.9   27  3,700

  1,860 1.1 4.6 >56,000

>100,000   150*   317†  1,100

 24,760   59   616 not tested

>100,000 67,247  57,075  not tested as no binding observed

 >10,000    43*    58† not tested

>100,000 23,320  20,950  not tested

  8,600   25   256    903

  8,851 9.8 28.1   46,000

  1,600 0.6 8.3 1.0

  5,824    29*    59† not tested

 42,000    58*   167† not tested

 17,240   288*  5,100† not tested

 >10,000 4.2 11.5  >10,000

 >10,000   368 1,935  16,000

 32,487   119   770 >10,000

 >10,000   102   358  >5,000

 34,950   352 1,838 >10,000 *HT-29(α_(2A)) †Rat Kidney Cortex (α_(2AB))

Several modifications of the above described compounds, the processesdisclosed for making them, and application of the disclosed processes tonumerous compounds beyond the examples set forth above, may be practicedby those skilled in the art without departing from the scope and spiritof the present invention. Therefore the scope of the present inventionshould be interpreted solely from the following claims, as such claimsare read in light of the present disclosure.

What is claimed is:
 1. A compound of formula I

in which: ring A is one of the five alternative multi-cyclic rings asshown wherein a dotted line adjacent to a bond indicates that a singlebond or a double bond may be present at that position; X is sulfur; R ishydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, orstraight or branched chain alkenyl of 2 to 6 carbon atoms, acycloaliphatic ring of 3 to 6 carbon atoms, phenyl optionally mono- ordi-substituted with hydroxy, halogen, alkyl of 1 to 3 carbon atoms oralkoxy of 1 to 2 carbon atoms, or methylenedioxyphenyl; or astereoisomer, or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1 wherein the ring A is bicyclo[2.2.1]heptane(norbornane).
 3. The compound of claim 2 wherein R is hydrogen; phenyloptionally mono- or di-substituted with hydroxy, halogen, alkyl of 1 to3 carbon atoms or alkoxy of 1 to 2 carbon atoms; ormethylenedioxyphenyl.
 4. A composition suitable for administration to amammal having a disease state which is alleviated by treatment with anα₂-blocking agent, the composition comprising a therapeuticallyeffective amount of a compound of formula I

in which: ring A is one of the five alternative multi-cyclic rings asshown wherein a dotted line adjacent to a bond indicates that a singlebond or a double bond may be present at that position; X is sulfur; R ishydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, orstraight or branched chain alkenyl of 2 to 6 carbon atoms, acycloaliphatic ring of 3 to 6 carbon atoms, phenyl optionally mono- ordi-substituted with hydroxy, halogen, alkyl of 1 to 3 carbon atoms oralkoxy of 1 to 2 carbon atoms, or methylenedioxyphenyl; or astereoisomer, or a pharmaceutically acceptable salt thereof, inadmixture with one or more pharmaceutically acceptable carriers.
 5. Thecomposition of claim 4 wherein the ring A is bicyclo [2.2.1] heptane(norbornane).
 6. The composition of claim 5 wherein R is hydrogen;phenyl optionally mono- or di-substituted with hydroxy, halogen, alkylof 1 to 3 carbon atoms or alkoxy of 1 to 2 carbon atoms; ormethylenedioxyphenyl.
 7. A method for treating a mammal having a diseasestate, wherein said disease state is elevated intraocular pressure,which is alleviated by treatment with an a blocking agent, whichcomprises administering a therapeutically effective amount of a compoundof formula I

in which: ring A is one of the five alternative multi-cyclic rings asshown wherein a dotted line adjacent to a bond indicates that a singlebond or a double bond may be present at that position; X is sulfur; R ishydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, orstraight or branched chain alkenyl of 2 to 6 carbon atoms, acycloaliphatic ring of 3 to 6 carbon atoms, phenyl optionally mono- ordi-substituted with hydroxy, halogen, alkyl of 1 to 3 carbon atoms oralkoxy of 1 to 2 carbon atoms, or methylenedioxyphenyl; or astereoisomer, or a pharmaceutically acceptable salt thereof.
 8. Themethod of claim 7 wherein said disease state is elevated intraocularpressure.
 9. The method of claim 7 wherein the ring A is bicyclo [2.2.1]heptane (norbornane).
 10. The method of claim 9 wherein R is hydrogen;phenyl optionally mono- or di-substituted with hydroxy, halogen, alkylof 1 to 3 carbon atoms or alkoxy of 1 to 2 carbon atoms; ormethylenedioxyphenyl.